CD45 inhibition in myeloid leukaemia cells sensitizes cellular responsiveness to chemotherapy
Bibliographic record
Abstract
Abstract Background Myeloid malignancies are a group of blood disorders characterized by the proliferation of one or more haematopoietic myeloid cell lineages, predominantly in the bone marrow and are often caused by aberrant protein tyrosine kinase activity. The protein tyrosine phosphatase CD45 is a transmembrane molecule expressed on all haemopoietic blood cells except that of platelets and red cells. CD45 regulates various cellular physiological processes including proliferation, apoptosis, and lymphocyte activation. The aim of this study was to investigate the role of CD45 in myeloid malignancies in terms of cellular growth, apoptosis, and response to chemotherapy to investigate alternative therapies with less toxicity and more efficacy. Methods The expression profile of CD45 was established in a panel of myeloid leukaemia cell lines and in peripheral blood cells from normal individuals, AML and MPN patients using western blot, flow cytometry, and PCR. CD45 KD was performed by using siRNA nucleofection and lipofectamine RNAiMAX technology. Bioinformatics study was performed using Partek Genomic Suit and Quadratic software for connectivity mapping. RNA sequencing was performed on CD45 KD cells and CD45 inhibited cells versus control cells. Apoptosis was studied by using Caspase-Glo™ Assay and western blotting. Drug combination studies between CD45 inhibitors and chemotherapy were performed and cytotoxicity was estimated by using Cell Titer-Glo® (CTG). Results The expression of CD45 on myeloid leukaemia primary cells and cell lines was heterogeneous with HEL and OCI-AML3 cells showing the highest level. Knockdown (KD) and/or inhibition of CD45 resulted in increased cellular sensitivity to cytarabine and ruxolitinib. Bioinformatics analysis identified of alendronate, allopurinol, and balsalazide as CD45 inhibitors along with genes whose expression was correlated with CD45 expression such as JAK2, ACTR2, THAP3 Serglycin and PBX-1 genes. Conclusions CD45 inhibition could be explored as a potential therapeutic partner for treatment of myeloid malignancies in combination with chemotherapy such as cytarabine. Identification of alendronate, allopurinol, and balsalazide, licensed drugs, could be repurposed as CD45 inhibitors at non-toxic concentrations which effectively increases sensitivity to cytarabine and ruxolitinib at low doses. Therefore, combining CD45 inhibitor drugs with low dose chemotherapy can be beneficial in treating myeloid leukaemia and can provide an alternative therapy characterized by less toxicity and more efficiency especially for elderly patients and those showing chemotherapy resistance.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".